Functional signatures of protective antiviral T-cell immunity in human virus infections

Summary: The most common human viruses have different abilities to establish persistent chronic infection. Virus‐specific T‐cell responses are critical in the control of virus replication and in the prevention of disease in chronic infection. A large number of phenotypic markers and a series of functions have been used to characterize virus‐specific CD4⁺ and CD8⁺ T‐cell responses, and these studies have shown great phenotypic and functional heterogeneity of the T‐cell responses against different viruses. The heterogeneity of the T‐cell response has been proposed to be specific to each virus. However, over the past 2 years, several studies have provided evidence that the phenotypic and functional heterogeneity of CD4⁺ and CD8⁺ T‐cell responses is predominantly regulated by the levels of antigen load. The levels of antigen load modulate the phenotypic and functional patterns of the T‐cell response within the same virus infection. Furthermore, the functional characterization of virus‐specific CD4⁺ and CD8⁺ T‐cell responses has identified signatures of protective antiviral immunity. Polyfunctional, i.e. interleukin‐2 and interferon‐γ (IFN‐γ) secretion and proliferation, and not monofunctional, i.e. IFN‐γ secretion, CD4⁺ and CD8⁺ T‐cell responses represent correlates of protective antiviral immunity in chronic virus infections.     

The Parkinson-Control study: a 1-year randomized, double-blind trial comparing piribedil (150 mg/day) with bromocriptine (25 mg/day) in early combination with levodopa in Parkinson's disease.

Dopamine agonists have been recommended as early treatment for Parkinson's disease (PD), alone or combined with levodopa. Piribedil is a non-ergot selective D(2)/D(3) agonist with alpha(2) antagonist properties shown to be effective in the treatment of PD. This 12-month international, randomized, double-blind trial aimed to assess the efficacy of piribedil 150 mg versus bromocriptine 25 mg, in early combination with levodopa in Stage I to III PD patients. Motor efficacy was assessed using the Unified Parkinson's Disease Rating Scale (UPDRS III, Items 18-31) as improvement from baseline. Response rate was defined as a 30% improvement. Among the 425 randomly assigned patients, 178 were also included in a substudy on cognitive follow-up evaluated by a dysexecutive syndrome oriented battery. A relevant improvement in UPDRS III over the 12-month study duration was observed both in the piribedil and bromocriptine groups (-7.9 +/- 9.7 points from baseline versus -8.0 +/- 9.5; not significant [n.s.]) with a response rate of 58.4% and 55.3% (n.s.), respectively. Piribedil and bromocriptine resulted in similar improvement on all UPDRS III subscores. Piribedil patients required less levodopa dose increase than those on bromocriptine. Cognitive performance remained generally unchanged in both groups, with a significant effect of piribedil limited to the Wisconsin Card Sorting Test. An overall good tolerability of piribedil was observed. Early combination of piribedil 150 mg with levodopa resulted in significant long-term improvement of all motor symptoms in PD patients insufficiently controlled by levodopa alone. Taking into account both efficacy and acceptability in the long-term, piribedil proved in this bromocriptine controlled study to be an effective and safe treatment for PD.     

1,3-Dipropyl-8-cyclopentylxanthine attenuates the NMDA response to hypoxia in the rat hippocampus

Excitatory amino acids may cause neuronal damage and death in cerebral hypoxia and ischemia, through the activation of different subtypes of glutamate receptors, in particular of the (NMDA) receptor. In the present work, the effect of hypoxia on the component of the field excitatory postsynaptic potential (fepsp) mediated by the NMDA receptor was studied in the hippocampal CA1 area of the rat. A period of 15 min of hypoxia induced virtual abolition of the NMDA receptor-mediated fepsp and a 94.8 ± 0.7% maximal decrease in the fepsp. A period of 3 min of hypoxia induced a 89.3 ± 12.3% maximal decrease in the NMDA receptor-mediated component of the fepsp and only a 50.8 ± 11.5% maximal decrease in the fepsp. Both periods of hypoxia thus induced a more pronounced depression of the NMDA receptor-mediated component of the fepsp than of the fepsp. We found that 48.5 ± 9.1% decrease (about half of the total decrease) in the NMDA receptor-mediated fepsp, and 51.6 ± 19.6% decrease (approximately all decrease) in the fepsp induced by hypoxia (3 min) were reversed in the presence of the selective adenosine A₁ receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) (50 nM), and thus likely to be mediated by endogenous adenosine, through the activation of adenosine A₁ receptors. On the other hand, under the conditions we assumed to be normoxic in our slices, DPCPX (50 nM) induced a much larger increase in the amplitude of the NMDA receptor-mediated fepsp compared to the increase in the fepsp, which suggest that endogenous adenosine is inhibiting predominantly the NMDA receptor-mediated fepsp under these conditions. Hypoxia markedly decreases the NMDA receptor-mediated fepsp in the hippocampal CA₁ area. The contribution of endogenous adenosine to the inhibition of the NMDA receptor-mediated fepsp may be fundamental for its neuroprotective effects.     

Kidney transplantation in patients with Wilms' tumor.

We report our experience of renal transplantation in three patients treated for Wilms' tumor (with lung metastasis in two of them), and review 26 previously reported cases in order to define the current indications of transplantation in this setting. Our patients, aged 5-12 years, were transplanted 13-95 months after completion of Wilms' tumor treatment. All three are alive and tumor-free, two with a functioning graft 20 and 97 months after transplantation. Two findings emerge from the review of the literature. First, posttransplant mortality is influenced by the delay between completion of tumor treatment and transplantation. Mortality reaches 79% when that delay is less than one year but falls to 27% when that delay exceeds one year. Second, the prognostic value of pretransplant metastasis depends on its location. All four patients with pretransplant abdominal metastasis died with active metastatic disease. By contrast, of three patients treated before transplantation for metastasis confined to the lung, two are alive and tumor free. We conclude that renal transplantation should be offered to patients successfully treated for Wilms' tumor for at least one year, even if the disease has been complicated by pulmonary metastasis. Several long-term survivors attest that the disease can be cured even under maintenance immunosuppression.     

Ischemic stroke complicating cardiac catherization: case report.

Ischemic stroke occurs in 0.2-0.4% of patients undergoing left heart catheterization, and is responsible for 5-10% of the mortality associated with the procedure. The main predisposing factors for this complication are female gender, complex atherosclerotic plaques in the ascending aorta, and peripheral arterial disease. The possibility of timely intervention with reperfusion therapy supports close clinical monitoring during the immediate post-catheterization period. The cardiologist should be familiar with the various types of stroke reperfusion therapy and its indications according to the time interval between catheterization and the stroke. The decision should be discussed with neurology and neuroradiology.     

Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial.

AIMS: To evaluate the efficacy and safety of ezetimibe 10 mg administered with pravastatin in patients with primary hypercholesterolemia. METHODS AND RESULTS: After dietary stabilization, 2-12 week screening/washout period, and 4-week, single-blind, placebo lead-in period, 538 patients with baseline LDL-C > or =3.8 to < or =6.5 mmol/l and TG < or =4.0 mmol/l were randomized to one of eight possible treatments administered daily for 12 weeks: ezetimibe 10mg; pravastatin 10, 20, or 40 mg; ezetimibe 10 mg plus pravastatin 10, 20, or 40 mg; or placebo. The primary efficacy endpoint was percent reduction in LDL-C from baseline to study endpoint for ezetimibe 10 mg plus pravastatin (pooled doses) compared to pravastatin alone (pooled doses) and ezetimibe alone. The combined use of ezetimibe and pravastatin resulted in significant incremental reductions in LDL-C and TG compared to pooled pravastatin alone (p<0.01). Coadministration therapy reduced LDL-C by 34-41%, TG by 21-23%, and increased HDL-C by 7.8-8.4%, depending on the dose of pravastatin. The combined regimen was well tolerated, with a safety profile similar to pravastatin alone and placebo. CONCLUSIONS: When coadministered with pravastatin, ezetimibe provided significant incremental reductions in LDL-C and TG and was well tolerated with a safety profile similar to pravastatin alone.